Mosmann et al., proposed that helper T cells (Th), lymphocytes playing a central role in immune responses, could be classified into two subsets, Th1 and Th2 cells, according to secretion patterns of cytokines [J. Immunol., vol. 136, p. 2348 (1986)]. Since then, several reports indicating that abnormality in the balance of Th1 and Th2 cells is closely involved in onset and aggravation of diseases caused by immune malfunction such as allergic diseases and autoimmune diseases and of diseases associated with immune malfunction have been published [Medical Immunology, vol. 15, p. 401 (1988); Annual Review of Immunology, vol. 12, p. 227 (1994); and Immunology Today, vol. 17, p. 138 (1996)].
Among the diseases above, allergic diseases are believed to be caused mainly by an increase in the number and the accentuation of Th2 cells, and an increase in production of IgE antibodies, IL-4 and IL-5 are said to be one of the aggravation factors. IL-4, one of cytokines produced in Th2 cell, accelerates production of IgE antibodies, while IL-5 accelerates differentiation, proliferation and migration of acidocytes, and also has a life-extending effect on the cells. Therefore, a medicine to suppress the functions of Th2 cell has a potential to relieve symptoms of the allergic diseases. Antiallegic drugs currently available, mainly suppressing immediate allergic responses, are not so effective for late-onset allergic diseases such as severe asthma and atopic dermatitis in the allergic diseases. Steroid drugs are often used for that purpose, but various side effects associated with taking such drugs for a long period of time (such as steroid skin diseases, adrenal cortical incompetence, etc.) are cited as the disadvantage.
Additionally, cyclosporin and tacrolimus are also used as the immunosuppressive drugs, but these drugs are non-specific, i.e., suppressing immune responses of Th2 side as well as Th1 side, and thus the administration thereof often lead to deterioration in resistance to infection and cause severe side effects such as nephrotoxicity and hepatotoxicity. Condensed heterocyclic compounds having suppressive activities to the Th2 immune responses have been described in JP 10-298181 A, JP 10-324631 A, JP 10-330369 A, WO98/47899 and J. Immunol., 162, 7470 (1999), but hitherto, no condensed pyrazole derivatives having the suppressive activity to the Th2 immune responses have been reported.
Pyrazolo[3,4-b]pyridine derivatives relevant to the present invention have been described in JP 48-57995 A (1973), JP 48-81891 A, U.S. Pat. No. 3,840,546 (1974), and Arch. Pharma., vol. 307, p. 117 (1974).
Non-steroidal anti-inflammatory drugs (NSAIDs) have been widely used for treatment of the inflammatory diseases such as inflammation, pain, fever, but these drugs also have clinical disadvantage in that they are not free from the side effect of gastrointestinal disorders adequately.
Recently, a hypothesis that cyclooxygenase (COX), the site of action of the non-steroidal anti-inflammatory agents, has two isozymes, COX-1 and COX-2, and inhibition of the COX-1, the constitutive enzyme thereof, could trigger gastrointestinal disorders was proposed. Since then, development of a COX-2 selective inhibitor has been intensively carried out to overcome the problems of gastrointestinal disorders. Consequently, Celecoxib and Rofecoxib are brought on the market in 1999, from Searle and Merck respectively, as NSAIDs that have fewer problems of the gastrointestinal disorders. But, a fact that a COX-1 knock-out mouse does not have gastric disorder was pointed out, for example, in Cell, vol. 83, p. 483 (1995), and a fact that even the COX-1 selective inhibitors have fewer cases of stomach disorders if they do not induce apoptosis of the gastric mucosal cells was also reported in Eur. J. Pharm., vol. 380, p. 271 (1998), and thus there is still doubt in that the COX-2 selective inhibitor can completely conquer the problem of the gastrointestinal disorders.